Method for preventing or treating skin tumor

ABSTRACT

Methods, compositions and products for preventing skin tumor formation or inhibiting development of an existing skin tumor in a subject are described. The methods involve administering to the subject a composition containing an α2 adrenergic receptor agonist, such brimonidine.

BACKGROUND OF THE INVENTION

UV radiation has been shown to be a cause for a wide spectrum of skindamage, from premature aging to skin cancer, the most prevalent of allcancers in the United States. Skin cancer is a malignant neoplasm of theepidermis/dermis, i.e., it has uncontrolled growth, invades nearbytissue, and if left untreated, may spread throughout the body,metastasizing and eventually killing the host. Basal cell and squamouscell carcinomas represent the majority of skin cancer cases. The leadingcause of death due to skin cancer is from malignant melanoma. It isestimated that over the lifetime 20% of United States population willdevelop skin cancer.

Besides skin cancer, there are also benign skin tumors and pre-malignantskin tumors. A benign skin tumor will not transform into skin cancer.Examples of benign skin tumors include, but are not limited to, moles,seborrheic keratoses, acrochordons (also called skin tags), epidermoidor sebaceous cysts, and dermatofibroma. A pre-malignant skin tumor is aconfined mass that does not invade surrounding tissue, and is thus notyet cancerous by definition. However, over time they can dedifferentiateand become malignant. One common form of pre-malignant cancer iscarcinoma in situ, where the cells are neoplastic and continue tomultiply, but do not leave their confined space.

Skin tumors can be treated by various therapies, such as surgicalremoval or destruction via excision, cryosurgery, electro-cautery,chemo-cautery, and radiation or topical cytotoxic agents. If themalignant skin tumors are detected early, treatment is usuallyeffective. However, the treatment can still be invasive.

An alpha adrenergic agonist is a drug that selectively stimulates alphaadrenergic receptors. The alpha-adrenergic receptor has two subclassesα1 and α2. Complete selectivity between receptor agonism is rarelyachieved, some agents have partial selectivity.

The α adrenoceptor agonists have been used therapeutically for a numberof conditions including hypertension, congestive heart failure, anginapectoris, spasticity, glaucoma, diarrhea, and for the suppression ofopiate withdrawal symptoms (J. P. Heible and R. R. Ruffolo TherapeuticApplications of Agents Interacting with α-Adrenoceptors, p. 180-206 inProgress in Basic and Clinical Pharmacology Vol. 8, P. Lomax and E. S.Vesell Ed., Karger, 1991).

It was reported that activation of alpha-adrenoceptors withalpha-adrenoceptor agonists (e.g., clonidine, oxymetazoline,dexmedetomidine, etc) was associated with enhanced proliferation ofhuman tumor epithelial breast cell lines or mouse mammary tumor cellline. See, e.g., Vázquez et al., Cancer Chemother Pharmacol. 2006 July;58(1):50-61. Epub 2005 Nov. 15; and Bruzzone et al., Br J Pharmacol.2008 October; 155(4):494-504. Epub 2008 Jul. 7. It was also reportedthat the alpha2-adrenoceptor antagonist yohimbine inhibited theproliferation and induced apoptosis of pancreatic cancer cells,suggesting that yohimbine can be used as an anticancer drug forpancreatic cancer. Shen et al., World J. Gastroenterol. 2008 Apr. 21;14(15):2358-63. It was further reported that stimulation of alpha2-adrenergic receptor inhibited cholangiocarcinoma, a cancer of the bileducts. Kanno et al., Hepatology, 2002, Volume 35, Issue 6 (p 1329-1340).The current literature, while not extensive, does indicate that thatalpha-adrenergic receptors may play a role in tumorogenesis, and thatstimulation or antagonism of the these receptors can lead to eitherincreased growth or suppression of tumor tissue, depending on theunderlying cellular sub-type.

There is a need of improved noninvasive methods and compositions thatwould effectively prevent skin tumor formation or reduces skin tumordevelopment, particularly for skin tumors induced by UV radiation. Thepresent invention relates to such improved methods and compositions.

BRIEF SUMMARY OF THE INVENTION

It is now surprisingly discovered that treatment with an α2 adrenergicreceptor agonist has resulted in a significant delay of skin tumorformation and a significant regression in skin tumor growth in subjectsexposed to UV radiation.

In one general aspect, embodiments of the present invention relate to amethod of preventing skin tumor formation in a subject. The methodcomprises administering to the subject a composition comprising aneffective amount of an α2 adrenergic receptor agonist and apharmaceutically acceptable carrier.

In another general aspect, embodiments of the present invention relateto a method of inhibiting the progression of an existing skin tumor in asubject, comprising administering to the subject a compositioncomprising a therapeutically effective amount of an α2 adrenergicreceptor agonist and a pharmaceutically acceptable carrier.

In another general aspect, embodiments of the present invention relateto a method of inducing the death or inhibiting the growth of a skintumor cell, comprising contacting the skin tumor cell with a compositioncomprising an α2 adrenergic receptor agonist in an amount sufficient toinduce the death or inhibit the growth of the skin tumor cell,respectively.

In another general aspect, embodiments of the present invention relateto a method for protecting the skin, the lips, or the scalp of a subjectagainst the damaging effects of UV-radiation. The method comprisesadministering to the subject a composition comprising a safe andeffective amount of an α2 adrenergic receptor agonist.

In another general aspect, embodiments of the present invention relateto a method of tanning the skin of a subject, wherein the methodcomprises administering to the subject a composition comprising a safeand effective amount of an α2 adrenergic receptor agonist.

Another aspect of the present invention relates to a cosmetic product,comprising:

(1) a topical composition comprising a safe and effective amount of anα2 adrenergic receptor agonist; and

(2) instructions on applying the topical composition to the skin, thelips, or the scalp of a subject against the damaging effects ofUV-radiation.

Yet another aspect of the present invention relates to a topicalcomposition for tanning the skin of a subject, comprising:

(1) a safe and effective amount of an α2 adrenergic receptor agonistand;

(2) a safe amount of a tanning agent.

Other aspects, features and advantages of the invention will be apparentfrom the following disclosure, including the detailed description of theinvention and its preferred embodiments and the appended claims.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1. Group Comparisons of Tumor Prevalence

DETAILED DESCRIPTION OF THE INVENTION

Various publications, articles and patents are cited or described in thebackground and throughout the specification; each of these references isherein incorporated by reference in its entirety. Discussion ofdocuments, acts, materials, devices, articles or the like which has beenincluded in the present specification is for the purpose of providingcontext for the present invention. Such discussion is not an admissionthat any or all of these matters form part of the prior art with respectto any inventions disclosed or claimed.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this invention pertains. Otherwise, certain terms usedherein have the meanings as set in the specification. All patents,published patent applications and publications cited herein areincorporated by reference as if set forth fully herein. It must be notedthat as used herein and in the appended claims, the singular forms “a,”“an,” and “the” include plural reference unless the context clearlydictates otherwise.

As used herein, an “α2 adrenergic receptor agonist” or “agonist of α2adrenoceptor” means a compound that binds to and stimulates alphaadrenergic receptor subclass α₂.

As used herein, the name of a compound is intended to encompass allpossible existing isomeric forms (e.g., optical isomer, enantiomer,diastereomer, racemate or racemic mixture), esters, prodrugs, metaboliteforms, or pharmaceutically acceptable salts, of the compound. Forexample, “brimonidine” can be the compound(5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine, and anypharmaceutically acceptable salt of the compound, such as brimonidinetartrate.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, meansthose salts of a compound of interest that are safe and effective fortopical use in mammals and that possess the desired biological activity.Pharmaceutically acceptable salts include salts of acidic or basicgroups present in the specified compounds. Pharmaceutically acceptableacid addition salts include, but are not limited to, hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate,tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate,p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compoundsused in the present invention can form pharmaceutically acceptable saltswith various amino acids. Suitable base salts include, but are notlimited to, aluminum, calcium, lithium, magnesium, potassium, sodium,zinc, and diethanolamine salts. For a review on pharmaceuticallyacceptable salts see BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1977),incorporated herein by reference.

As used herein, the term “hydrate” means a compound of interest, or apharmaceutically acceptable salt thereof that further includes astoichiometric or non-stoichiometric amount of water bound to it bynon-covalent intermolecular forces.

In an embodiment of the present invention, the α2 adrenergic receptoragonists include, but are not limited to, the α2 adrenergic receptoragonists disclosed in the published US Patent Application US20050276830,which is herein incorporated by reference in its entirety.

Representative α2 adrenergic receptor agonists that can be used in thepresent invention include, but are not limited to, those listed in Table1.

TABLE 1 Representative α2 adrenergic receptor agonists Compound CompoundFormula Name

(5-Bromo- quinoxalin- 6-yl)-(4,5- dihydro-1H- imidazol-2-yl)- amine(Brimonidine)

(8-Bromo- quinoxalin- 6-yl)-(4,5- dihydro-1H- imidazol-2-yl)- amine

(8-Bromo- quinoxalin- 5-yl)-(4,5- dihydro-1H- imidazol-2-yl)- amine

(5-Bromo-3- methyl- quinoxalin-6-yl)- (4,5-dihydro-1H- imidazol-2-yl)-amine

(5-Bromo-2- methoxy- quinoxalin-6-yl)- (4,5-dihydro-1H- imidazol-2-yl)-amine

(4,5-dihydro-1H- imidazol-2-yl)- (8-methyl- quinoxalin-6-yl)- amine

(4,5-dihydro-1H- imidazol-2-yl)- quinoxalin-5-yl- amine

Tetrahydrozaline

Naphazoline

Oxymetazoline

Xylometazoline

Epinephrine

Norepinephrine

Phenylephrine

Methoxyamine

The most preferred α2 adrenergic receptor agonist is brimonidine,(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine andpharmaceutically acceptable salts thereof, such as the tartrate salt ofbrimonidine.

Other examples of α2 adrenergic receptor agonists that can be used inthe present invention include, but are not limited to, Dexmedetomidine,Medetomidine, Romifidine, Clonidine, Detomidine, Lofexidine, Xylazine,Tizanidine, Guanfacine, and Amitraz.

According to the present invention, α2 adrenergic receptor agonists canbe administered to the subject through the routes of topical,epicutaneous, transdermal, subcutaneous, or intramuscular deliveries. Ina preferred embodiment, α2 adrenergic receptor agonists are delivery tothe site of the tumor or the skin area subject to UV damages bysubcutaneous delivery or topical application on the skin.

As used herein, “topical application” and “topically applying” meansdirectly laying on or spreading on the skin in need of treatment, e.g.,by use of the hands or an applicator.

As used herein, “subcutaneous delivery” means directly depositing in orunderneath the skin, or in the subcutaneous fat layer, by use of anapplicator such as a needle, a multi-needle array, an energy-baseddelivery system capable of subcutaneous delivery, a pressure-baseddelivery system capable of subcutaneous delivery, a needleless deliverysystem capable of subcutaneous delivery, or a similar medical device.

As used herein, an “skin tumor” includes a skin cancer, a benign skintumor and pre-malignant skin tumor. Skin cancers include, but are notlimited to, basal cell and squamous cell carcinomas and malignantmelanoma. Examples of benign skin tumors include, but are not limitedto, moles, seborrheic keratoses, acrochordons (also called skin tags),epidermoid or sebaceous cysts, and dermatofibroma. Pre-malignant skintumors include, but are not limited to carcinoma in situ.

One embodiment of the present invention relates to a method ofpreventing skin tumor formation in a subject, which comprisesadministering to the subject a composition comprising an effectiveamount of an α2 adrenergic receptor agonist and a pharmaceuticallyacceptable carrier.

As used herein, an “effective amount of an α2 adrenergic receptoragonist” means the amount of the α2 adrenergic receptor agonist that issufficient to prevent or delay the formation of skin tumors in a tissuesystem, mammal or human.

As used herein, the term “subject” means any mammal, preferably a human,to whom will be or has been administered compounds or topicalformulations according to embodiments of the invention.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

As used herein, “prevention” or “preventing” refers to a reduction ofthe risk of acquiring a skin tumor. In a preferred mode of theembodiment, the specified compounds are administered as a preventativemeasure to a subject having a predisposition to a skin tumor, eventhough symptoms of the disorder are absent or minimal.

As used herein, a “pharmaceutically-acceptable carrier” means a carrierthat is suitable for the application of the present invention withoutundue toxicity, incompatibility, instability, irritation, allergicresponse, and the like. This term is not intended to limit theingredient which it describes.

Another embodiment of the present invention relates to a method ofinhibiting the progression of an existing skin tumor in a subject, whichcomprises administering to the subject a composition comprising atherapeutically effective amount of an α2 adrenergic receptor agonistand a pharmaceutically acceptable carrier.

As used herein, a “therapeutically effective amount of an α2 adrenergicreceptor agonist” means the amount of the α2 adrenergic receptor agonistthat is sufficient to prevent or delay the progression of skin tumors ina tissue system, mammal or human.

One skilled in the art will recognize that the therapeutically effectiveamount of the α2 adrenergic receptor agonist to be used in the instantinvention can vary with factors, such as the particular subject, e.g.,age, diet, health, etc., degree of UV radiation exposed to, severity andcomplications of the skin tumor sought to be treated or prevented, theformulation used, etc. In view of the present disclosure, standardprocedures can be performed to evaluate the effect of the administrationof a composition to a subject, thus allowing a skilled artisan todetermine the therapeutically effective amount of the α2 adrenergicreceptor agonist to be administered to the subject. For example, theclinically observable beneficial effect of the α2 adrenergic receptoragonist in preventing the formation or preventing or delaying theprogression of a skin tumor.

The clinically observable beneficial effect can be a situation that,when a composition of the present invention is administered to a subjectafter signs and/or symptoms related to a skin tumor are observable, thesigns and/or symptoms are prevented from further development oraggravation, or develop to a lesser degree than without administrationof the specified composition according to embodiments of the presentinvention. The clinically observable beneficial effect can also be that,when a composition of the present invention is administered to a subjectbefore signs and/or symptoms related to a skin tumor are observable, thesigns and/or symptoms are prevented from occurring or subsequently occurto a lesser degree than without administration of the composition of thepresent invention.

In another embodiment, a therapeutically effective amount of the α2adrenergic receptor agonist will reduce of the discomfort of the subjectassociated with the skin tumor or a sign and/or symptom associatedtherewith.

Methods of the present invention can be used in conjunction with one ormore other treatments or medications for preventing the formation of askin tumor or inhibiting the progression, or treating an existing skintumor or a sign and/or symptom associated therewith.

For example, a therapeutically effective amount of an α2 adrenergicreceptor agonist can be used in conjunction with a therapy for treatinga skin tumor, such as surgery-scalpel, cryosurgery, electro-surgery,chemo-surgery, or radiation and cytotoxic agents, such as alkylatingagents, e.g., nitrogen mustard, ethyleneimine, fluorouracil,icyclophosphamide; anti-metabolites, e.g., 8-azaguinine,6-mercaptopurine, aminopterin, methotrexate; antibiotics, e.g.,sarcomycin, adinomycin, carcinophyrin, mitomycin-C, chromomycin,bleomycin, vinblastine; hormones, e.g., sex hormones, ACTH,corticosteroids; radio-isotopes—P 32, 1131, Co 60, Au 190; or plantderivatives, e.g., podophyllin, colchicin, milkweed, or Abrusprecatorius.

The other medicament or treatment can be administered to the subjectsimultaneously with, or in a sequence and within a time interval of, theadministration of the α2 adrenergic receptor agonist, such that theactive ingredients or agents can act together to treat or prevent skintumor and signs and/or symptoms associated therewith. For example, theother medicament or treatment and the α2 adrenergic receptor agonist canbe administered in the same or separate formulations at the same ordifferent times.

Any suitable route of administration can be employed to deliver theadditional treatment or medication including, but not limited to, oral,intraoral, rectal, parenteral, topical, epicutaneous, transdermal,subcutaneous, intramuscular, intranasal, sublingual, buccal, intradural,intraocular, intrarespiratory, or nasal inhalation.

Another embodiment of the present invention relates to a method ofinducing the death or inhibiting the growth of a skin tumor cell, whichcomprises contacting the skin tumor cell with a composition comprisingan α2 adrenergic receptor agonist in an amount sufficient to induce thedeath or inhibit the growth of the skin tumor cell, respectively. Thecell under the treatment can be in a cell culture in vitro, or a cellwithin an mammal in vivo.

The present invention also relates to a method for protecting the skin,the lips or the scalp of a subject against the damaging effects ofUV-radiation, wherein the method comprises administering to the subjecta composition comprising a safe and effective amount of an α2 adrenergicreceptor agonist.

As used herein, safe and effective amount of an α2 adrenergic receptoragonist refers to an amount of an α2 adrenergic receptor agonistsufficient to protect the skin against the damaging effects ofUV-radiation, specifically the UV-induced skin tumors, but low enough toavoid serious side effects. The safe and effective amount of α2adrenergic receptor agonist will vary with the age, health andenvironmental UV exposure of the subject, the duration and nature of thetreatment, the specific ingredient, or composition employed, theparticular pharmaceutically-acceptable carrier utilized, and likefactors.

The α2 adrenergic receptor agonist can be administered together with asafe and effective amount of a sun screening agent, an agent thatabsorbs or reflects some of the UV radiation in sunlight to thus helpprotect the skin against sun or UV damages.

As used herein, “safe and effective” refers to an amount of a sunscreening agent sufficient to provide photo protection when thecomposition is applied but not so much as to cause any unacceptable sideeffects or skin reactions. The amount varies depending upon the sunscreening agent chosen and the desired Sun Protection Factor (SPF).Commercially available sunscreen products have SPF values ranging from 2to 40 or more. According to embodiments of the present invention, atopical composition comprises a safe and UV-damage protectivelyeffective amount of an α2 adrenergic receptor agonist, and about 1% toabout 20%, by weight, of a sun screening agent.

The suitable sun screening agent is capable of being commingled with theα2 adrenergic receptor agonist used in the present invention in a mannersuch that there is no interaction which would substantially reduce theefficacy of the composition for skin tumor prevention and/or treatmentand photoprotection. Numerous sun screening agents are suitable for usein combination with α2 adrenergic receptor agonist, including, but notlimited to: p-Aminobenzoic acid, its salts and its derivatives (ethyl,isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); Anthranilates(i.e., o-aminobenzoates; methyl, menthyl, phenyl, benzyl, phenylethyl,linalyl, terpinyl, and cyclohexenyl esters); Salicylates (amyl, phenyl,benzyl, menthyl, glyceryl, and dipropyleneglycol esters); Cinnamic acidderivatives (menthyl and benzyl esters, α-phenyl cinnamonitrile; butylcinnamoyl pyruvate); Dihydroxycinnamic acid derivatives (umbelliferone,methylumbelliferone, methylaceto-umbelliferone);Trihydroxy-Trihydroxycinnamic acid derivatives (esculetin,methylesculetin, daphnetin, and the glucosides, esculin and daphnin);Hydrocarbons (diphenylbutadiene, stilbene); Dibenzalacetone andbenzalacetophenone; Naphtholsulfonates (sodium salts of2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);Dihydroxy-naphthoic acid and its salts; o- andp-Hydroxybiphenyldisulfonates; Coumarin derivatives (7-hydroxy,7-methyl, 3-phenyl); Diazoles (2-acetyl-3-bromoindazole, phenylbenzoxazole, methyl naphthoxazole, various aryl benzothiazoles); Quininesalts (bisulfate, sulfate, chloride, oleate, and tannate); Quinolinederivatives (8-hydroxyquinoline salts, 2-phenylquinoline); Hydroxy- ormethoxy-substituted benzophenones; Uric and vilouric acids; Tannic acidand its derivatives (e.g., hexaethylether); (Butyl carbityl) (6-propylpiperonyl)ether; Hydroquinone; Benzophenones (Oxybenzene, Sulisobenzone,Dioxybenzone, Benzoesorcinol, 2,2′,4,4′-Tetrahydroxybenzophenone,2,2′-Dihydroxy-4,4′-dimethoxybenzophenone, Octabenzone;4-Isopropyldibenzoylmethane; Butylmethoxydibenzoylmethane; Etocrylene;and 4-isopropyl-di-benzoylmethane. See, e.g., Segarin, et al., atChapter VIII, pages 189 et seq., of Cosmetics Science and Technology.

Preferred sun screening agents useful in the compositions of the presentinvention include, e.g., 2-ethylhexyl p-methoxycinnamate, butylmethoxydibenzoylmethane, 2-hydroxy-4-methoxybenzophenone, octyl dimethylp-aminobenzoic acid and mixtures thereof.

Another aspect of the present invention relates to a composition and amethod of tanning the skin of a subject, wherein the method comprisesadministering to the subject the composition comprising a safe andeffective amount of an α2 adrenergic receptor agonist.

As used herein, safe and effective amount of an α2 adrenergic receptoragonist refers to an amount of an α2 adrenergic receptor agonistsufficient to protect the skin against the damaging effects ofUV-radiation, specifically the UV-induced skin tumors, but low enough toavoid serious side effects. The safe and effective amount of α2adrenergic receptor agonist will vary with the tanning agent and theconcentration thereof used with herein, the duration and nature of UVexposure by the subject, the duration and nature of the treatment, thespecific ingredient, or composition employed, the particularpharmaceutically-acceptable carrier utilized, and like factors.

The α2 adrenergic receptor agonist can be administered together with asafe amount of a tanning agent, an agent that helps to increase and/orprolong skin tanning after exposure to natural or artificial sunlight.According to an embodiment of the present invention, a topicalcomposition for tanning the skin of a subject comprises a safe andeffective amount of an α2 adrenergic receptor agonist and a safe amountof a tanning agent.

The suitable tanning agent is capable of being commingled with the α2adrenergic receptor agonist used in the present invention in a mannersuch that there is no interaction which would substantially reduce theefficacy of the composition for skin tumor prevention and/or treatmentand skin tanning. Examples of the tanning agent that can be used in thepresent invention include, but are not limited to, tyrosine, riboflavin,collagen hydrolysate, and combinations thereof.

A composition according to embodiments of the present inventioncomprises an effective amount, or a therapeutically effective amount, ora safe and effective amount of an α2 adrenergic receptor agonist and apharmaceutically acceptable carrier.

In view of the present disclosure, the composition can be formulated forvarious delivery routes, such as topical, epicutaneous, transdermal,subcutaneous, or intramuscular deliveries. In a preferred embodiment,the α2 adrenergic receptor agonists is formulated as a subcutaneous ortopical formulation.

One embodiment of the present invention relates to a topical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of an α2 adrenergic receptor agonist. The carriersuseful for topical delivery of the specified compounds according toembodiments of the invention can be any carrier known in the art fortopically administering pharmaceuticals, including, but not limited to,pharmaceutically acceptable solvents, such as a polyalcohol or water;emulsions (either oil-in-water or water-in-oil emulsions), such ascreams or lotions; micro emulsions; gels; ointments; liposomes; powders;and aqueous solutions or suspensions. The pharmaceutically acceptablecarrier includes necessary and inert pharmaceutical excipients,including, but not limited to, binders, suspending agents, lubricants,flavorants, preservatives, dyes, and coatings.

The topical composition according to embodiments of the presentinvention are prepared by mixing a pharmaceutically acceptable carrierwith a therapeutically effective amount of an α2 adrenergic receptoragonist according to known methods in the art, for example, methodsprovided by standard reference texts such as, REMINGTON: THE SCIENCE ANDPRACTICE OF PHARMACY 1577-1591, 1672-167, 866-885(Alfonso R. Gennaro ed.19th ed. 1995); Ghosh, T. K.; et al. TRANSDERMAL AND TOPICAL DRUGDELIVERY SYSTEMS (1997), both of which are hereby incorporated herein byreference.

In one embodiment, the topical composition of the invention is in theform of an emulsion. Emulsions, such as creams and lotions are suitabletopical formulations for use in the invention. An emulsion is adispersed system comprising at least two immiscible phases, one phasedispersed in the other as droplets ranging in diameter from 0.1 μm to100 μm. An emulsifying agent is typically included to improve stability.When water is the dispersed phase and an oil is the dispersion medium,the emulsion is termed a water-in-oil emulsion. When an oil is dispersedas droplets throughout the aqueous phase as droplets, the emulsion istermed an oil-in-water emulsion. Emulsions, such as creams and lotionsthat can be used as topical carriers and their preparation are disclosedin REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 282-291 (Alfonso R.Gennaro ed. 19th ed. 1995), hereby incorporated herein by reference.

In another embodiment, the topical composition of the invention is inthe form of a gel, for example, a two-phase gel or a single-phase gel.Gels are semisolid systems consisting of suspensions of small inorganicparticles or large organic molecules interpenetrated by a liquid. Whenthe gel mass comprises a network of small discrete inorganic particles,it is classified as a two-phase gel. Single-phase gels consist oforganic macromolecules distributed uniformly throughout a liquid suchthat no apparent boundaries exist between the dispersed macromoleculesand the liquid. Suitable gels for use in the invention are disclosed inREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1517-1518 (Alfonso R.Gennaro ed. 19th ed. 1995), hereby incorporated herein by reference.Other suitable gels for use with the invention are disclosed in U.S.Pat. No. 6,387,383 (issued May 14, 2002); U.S. Pat. No. 6,517,847(issued Feb. 11, 2003); and U.S. Pat. No. 6,468,989 (issued Oct. 22,2002), each of which patents is hereby incorporated herein by reference.

In an embodiment, the topical composition further comprises an aqueousgel comprising water and a water-gelling amount of a pharmaceuticallyacceptable gelling agent selected from the group consisting ofcarbomers, glycerine polyacrylate, and mixtures thereof, and the topicalcomposition has a physiologically acceptable pH.

As used herein, “carbomer” is the USP designation for various polymericacids that are dispersible but insoluble in water. When the aciddispersion is neutralized with a base a clear, stable gel is formed.Carbomer 934P is physiologically inert and is not a primary irritant orsensitizer. Other carbomers include 910, 940, 941, and 1342. Polymerthickeners (gelling agents) that may be used in compositions accordingto embodiments of the present invention include those known to oneskilled in the art, such as hydrophilic and hydroalcoholic gellingagents frequently used in the cosmetic and pharmaceutical industries.Preferably, the hydrophilic or hydroalcoholic gelling agent comprises“CARBOPOL®” (B.F. Goodrich, Cleveland, Ohio), “HYPAN®” (KingstonTechnologies, Dayton, N.J.), “NATROSOL®” (Aqualon, Wilmington, Del.),“KLUCEL®” (Aqualon, Wilmington, Del.), or “STABILEZE®” (ISPTechnologies, Wayne, N.J.). Preferably the gelling agent comprisesbetween about 0.2% to about 4% by weight of the composition. Moreparticularly, the preferred compositional weight percent range for“CARBOPOL®” is between about 0.5% to about 2%, while the preferredweight percent range for “NATROLSOL®” and “KLUCEL®” is between about0.5% to about 4%. The preferred compositional weight percent range forboth “HYPAN®” and “STABILEZE®” is between 0.5% to about 4%.

“CARBOPOL®” is one of numerous cross-linked acrylic acid polymers thatare given the general adopted name carbomer. These polymers dissolve inwater and form a clear or slightly hazy gel upon neutralization with acaustic material such as sodium hydroxide, potassium hydroxide,triethanolamine, or other amine bases. “KLUCEL®” is a cellulose polymerthat is dispersed in water and forms a uniform gel upon completehydration. Other preferred gelling polymers includehydroxyethylcellulose, cellulose gum, MVE/MA decadiene crosspolymer,PVM/MA copolymer, or a combination thereof.

In another preferred embodiment, the topical composition of theinvention is in the form of an ointment. Ointments are oleaginoussemisolids that contain little if any water. Preferably, the ointment ishydrocarbon based, such as a wax, petrolatum, or gelled mineral oil.Suitable ointments for use in the invention are well known in the artand are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY1585-1591 (Alfonso R. Gennaro ed. 19th ed. 1995), hereby incorporatedherein by reference.

In an embodiment of the present invention, the topical composition ofthe invention comprises at least one of a cream and an ointment, eachcomprising an agent selected from the group consisting of stearic acid,stearyl alcohol, cetyl alcohol, glycerin, water, and mixtures thereof,and the topical composition has a physiologically acceptable pH.

In another embodiment, the topical composition of the invention is inthe form of an aqueous solution or suspension, preferably, an aqueoussolution. Suitable aqueous topical formulations for use in the inventioninclude those disclosed in REMINGTON: THE SCIENCE AND PRACTICE OFPHARMACY 1563-1576 (Alfonso R. Gennaro ed. 19th ed. 1995), herebyincorporated herein by reference. Other suitable aqueous topical carriersystems include those disclosed in U.S. Pat. No. 5,424,078 (issued Jun.13, 1995); U.S. Pat. No. 5,736,165 (issued Apr. 7, 1998); U.S. Pat. No.6,194,415 (issued Feb. 27, 2001); U.S. Pat. No. 6,248,741 (issued Jun.19, 2001); 6,465,464 (issued Oct. 15, 2002), all of which patents arehereby incorporated herein by reference.

The pH of the topical formulations of the invention are preferablywithin a physiologically acceptable pH, e.g., within the range of about5 to about 8, more preferably, of about 5.5 to about 6.5. To stabilizethe pH, preferably, an effective amount of a buffer is included. In oneembodiment, the buffering agent is present in the aqueous topicalformulation in an amount of from about 0.05 to about 1 weight percent ofthe formulation. Acids or bases can be used to adjust the pH as needed.

Tonicity-adjusting agents can be included in the aqueous topicalformulations of the invention. Examples of suitable tonicity-adjustingagents include, but are not limited to, sodium chloride, potassiumchloride, mannitol, dextrose, glycerin, and propylene glycol. The amountof the tonicity agent can vary widely depending on the formulation'sdesired properties. In one embodiment, the tonicity-adjusting agent ispresent in the aqueous topical formulation in an amount of from about0.5 to about 0.9 weight percent of the formulation.

Preferably, the aqueous topical formulations of the invention have aviscosity in the range of from about 15 cps to about 25 cps. Theviscosity of aqueous solutions of the invention can be adjusted byadding viscosity adjusting agents, for example, but not limited to,polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,carboxymethyl cellulose, or hydroxyethyl cellulose.

In a preferred embodiment, the aqueous topical formulation of theinvention is isotonic saline comprising a preservative, such asbenzalkonium chloride or chlorine dioxide, a viscosity-adjusting agent,such as polyvinyl alcohol, and a buffer system such as sodium citrateand citric acid.

The topical composition according to embodiments of the invention cancomprise pharmaceutically acceptable excipients such as those listed inREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 866-885(Alfonso R.Gennaro ed. 19th ed. 1995; Ghosh, T. K.; et al. TRANSDERMAL AND TOPICALDRUG DELIVERY SYSTEMS (1997), hereby incorporated herein by reference,including, but not limited to, protectives, adsorbents, demulcents,emollients, preservatives, antioxidants, moisturizers, buffering agents,solubilizing agents, skin-penetration agents, and surfactants.

In an embodiment, the topical composition of the invention furthercomprises one or more agent selected from the group consisting of apreservative, a local anesthetic and a skin humectant.

Suitable preservatives include, but are not limited to, quaternaryammonium compounds, such as benzalkonium chloride, benzethoniumchloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride;mercurial agents, such as phenylmercuric nitrate, phenylmercuricacetate, and thimerosal; alcoholic agents, for example, chlorobutanol,phenylethyl alcohol, and benzyl alcohol; antibacterial esters, forexample, esters of parahydroxybenzoic acid; and other anti-microbialagents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin.

The topical composition according to embodiments of the invention caninclude pharmaceuticals or their pharmaceutically acceptable salts, suchas an α2 adrenergic receptor agonist, and optionally one or more otherpharmaceutically active ingredients, including, but not limited to,corticosteroids and other anti-inflammatory agents, such asbetamethasone, diflorasone, amcinonide, fluocinolone, mometasone,hydrocortisone, prednisone, and triamcinolone; local anesthetics andanalgesics, such as camphor, menthol, lidocaine, and dibucaine, andpramoxine; antifungals, such as ciclopirox, chloroxylenol, triacetin,sulconazole, nystatin, undecylenic acid, tolnaftate, miconizole,clotrimazole, oxiconazole, griseofulvin, econazole, ketoconozole, andamphotericin B; antibiotics and anti-infectives, such as mupirocin,erythromycin, clindamycin, gentamicin, polymyxin, bacitracin, and silversulfadiazine; and antiseptics, such as iodine, povidine-iodine,benzalkonium chloride, benzoic acid, chlorhexidine, nitrofurazine,benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol,resorcinol, and cetylpyridinium chloride.

In a preferred embodiment, a topical composition according toembodiments of the invention further comprises titanium dioxide (TiO₂),preferably at an amount that is sufficient to mask the color ofbrimonidine or another colored ingredient in the formulation, but wouldnot cause irritation to the skin. TiO₂ may cause mild irritation andreddening to the eyes, thus eye contact with the TiO₂-containingtopically administrable composition should be avoided.

Dosages and dosing frequency will be determined by a trained medicalprofessional depending on the activity of the compounds used, thecharacteristics of the particular topical formulation, and the identityand severity of the dermatologic disorder treated or prevented.

In an embodiment of the present invention, the topical compositioncomprises 0.01% to 5% by weight of the α2 adrenergic receptor agonist.For example, the composition can comprise, 0.01%, 0.05%, 0.1%, 0.2%,0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4% or 5%, byweight, of the α2 adrenergic receptor agonist.

To treat or prevent a skin tumor in view of the present disclosure, forexample, the topical compositions of the invention are topically applieddirectly to the area exposed to sunlight or the otherwise affected areain any conventional manner well known in the art, e.g., by dropper orapplicator stick, as a mist via an aerosol applicator, via anintradermal or transdermal patch, or by simply spreading a formulationof the invention onto the affected area with fingers. Generally theamount of a topical formulation of the invention applied to the affectedskin area ranges from about 0.1 g/cm² of skin surface area to about 5g/cm², preferably, 0.2 g/cm² to about 0.5 g/cm² of skin surface area.Typically, one to four applications per day are recommended during theterm of treatment.

Another embodiment of the present invention relates to a cosmeticproduct, comprising:

(1) a topical composition comprising a safe and effective amount of anα2 adrenergic receptor agonist; and

(2) instructions on applying the topical composition to the skin, thelips, or the scalp of a subject against the damaging effects ofUV-radiation.

As used herein, the term “instructions” when used in the context of akit includes a publication, a recording, a diagram or any other mediumof expression which can be used to communicate the usefulness of the kitfor its designated use. The instructions can, for example, be affixed toor included within a container for the kit.

The cosmetic product can further comprise a second topical compositioncomprising a safe and effective amount of a sun screening agent.

The α2 adrenergic receptor agonist and the sun screening agent can beformulated in the same or separate topical compositions contained in oneor two separate containers, such as a dropper, a jar, or a tube with asuitable small orifice size, such as an extended tip tube, made of anypharmaceutically suitable material.

The topical formulations of the invention can be filled and packagedinto a plastic squeeze bottle or tube. Suitable container-closuresystems for packaging a topical formulations of the invention arecommercially available for example, from Wheaton Plastic Products, 1101Wheaton Avenue, Millville, N.J. 08332.

Preferably, instructions are packaged with the formulations of theinvention, for example, a pamphlet or package label. The labelinginstructions explain how to administer topical formulations of theinvention, in an amount and for a period of time sufficient to treat orprevent a skin tumor and signs and/or symptoms associated therewith.Preferably, the label includes the dosage and administrationinstructions, the topical formulation's composition, the clinicalpharmacology, drug resistance, pharmacokinetics, absorption,bioavailability, and contraindications.

This invention will be better understood by reference to thenon-limiting examples that follow, but those skilled in the art willreadily appreciate that the examples are only illustrative of theinvention as described more fully in the claims which follow thereafter.

Example 1 Aqueous Topical Formulations

This example illustrates aqueous topical formulations that can be usedin the present invention.

A first aqueous solution topical formulation comprises: brimonidinetartrate (0.01% to 5% w/w); Puriteg (0.005% w/w) (stabilized chlorinedioxide) as a preservative; and the inactive ingredients: boric acid;calcium chloride; magnesium chloride; potassium chloride; purifiedwater; sodium borate; sodium carboxymethylcellulose; sodium chloride;with hydrochloric acid and/or sodium hydroxide to adjust the pH to 5.6to 6.6. The osmolality is in the range of 250-350 mOsmol/kg.

A second aqueous solution topical formulation comprises brimonidinetartrate (0.2% to 2% w/w); benzalkonium chloride (0.005% w/w.) as apreservative; and the inactive ingredients: boric acid; calciumchloride; magnesium chloride; potassium chloride; purified water; sodiumborate; sodium carboxymethylcellulose; sodium chloride; withhydrochloric acid and/or sodium hydroxide to adjust the pH to 5.6 to6.6. The osmolality is in the range of 250-350 mOsmol/kg.

Example 2 Cream or Ointment Topical Formulations

This example illustrates cream or ointment topical formulations that canbe used in the present invention.

A first cream topical formulation (hydrophilic ointment) is described inTable 2 below.

TABLE 2 Ingredient Weight Percent Brimonidine tartrate 0.01% to 5%Stearic acid   7% Stearyl alcohol   5% Cetyl alcohol 2% Glycerin   10%Sodium lauryl sulfate   1% Propylparaben 0.05% Methylparaben 0.25%Disodium edetate 0.055%  Distilled water QS TOTAL  100%

To make the formulation, the stearyl alcohol and the white petrolatumare melted on a steam bath, and warmed to about 75 degrees C. The otheringredients, previously dissolved in the water and warmed to 75 degreesC., are then added, and the mixture is stirred until it congeals. Themixture is then allowed to cool with stirring, and brimonidine tartrateis then added as a concentrated solution.

An ointment topical formulation (hydrophilic ointment) is described inTable 3 below.

TABLE 3 Ingredients Weight Brimonidine tartrate 20 g Cholesterol 30 gStearyl Alcohol 30 g White Wax 80 g White Petrolatum 820-800 g

To make the formulation, the stearyl alcohol and white wax are mixedtogether on a steam bath. The cholesterol is then added and stirreduntil it completely dissolved. The white petrolatum is then added andmixed. The mixture is removed from the bath, and stirred until itcongeals. With continuous stirring, brimonidine tartrate is added as aconcentrated slurry.

Example 3 Gel Topical Formulations

This example illustrates gel topical formulations that can be used inthe present invention.

A first gel formulation is described in Table 4 below.

TABLE 4 Ingredients Weight % Brimonidine tartrate 0.01-5% MethylparabenNF 0.15% Propylparaben NF 0.03% Hydroxyethylcellulose NF 1.25% DisodiumEdetate USP 0.05% Purified Water, USP QS TOTAL  100%

A second gel formulation is described in Table 5 below.

TABLE 5 Ingredients Weight % Brimonidine tartrate  0.5% Methylparaben0.20% Propylparaben 0.05% Carbomer 934P NF  1.0% Sodium Hydroxide QS pH7 Purified Water, USP QS TOTAL  100%

The ingredients are mixed together and aqueous sodium hydroxide isslowly added to the mixture until a pH of about 7 is reached and the gelis formed.

A third gel formulation is described in Table 6 below.

TABLE 6 Ingredient Weight Percent Brimonidine tartrate 0.1-2% Carbomer934P 1.25%  Methylparaben 0.3% Phenoxyethanol 0.4% Glycerin 5.5% 10%Titanium dioxide 0.625%  Propylene glycol 5.5% 10% NaOH Solution 6.5% DIWater QS TOTAL 100% 

A fourth gel formulation is described in Table 7 below.

TABLE 7 Ingredients Weight % Brimonidine tartrate 0.01-5% Methylparaben0.2% Propylparaben 0.05%  “CARBOPOL ®” 1.0% Triethanolamine QS pH 7Water QS TOTAL 100%

The ingredients are mixed together and stirred. Triethanolamine is addeduntil a pH of about 7 is attained.

Example 4 Foam Topical Formulations

This example illustrates foam topical formulations that can be used inthe present invention.

A first foam formulation is described in Table 8 below.

TABLE 8 Ingredients Amount (Weight %) Brimonidine tartrate 0.01-5Stearic Acid 4.2 Laureth-23 1.4 Sodium Lauryl Sulfate 0.5Triethanolamine 2.2 Butylated hydroxytoluene (BHT) 0.01 Fragrance 0.5Aeron A-31 Propellant 3 Water QS TOTAL 100

The water is heated to 80-85° C., after which stearic acid is added.Once the stearic acid is melted, the laureth-23 is added, melted, andmixed well. Next, triethanolamine is added and the resulting compositionis mixed well for about 30 minutes to form a soap. The resulting soap isthen cooled to about 65° C., after which sodium lauryl sulfate is added.The composition is then mixed well. Next, the BHT and the Brimonidinetartrate are added, followed by mixing. The resulting composition isthen cooled to room temperature and the fragrance added. The product ispackaged with the Aeron A-31 propellant in an aerosol can usingconventional techniques and mechanically shaken for 5 minutes. Theproduct dispenses as a cone-shaped spray that deposits onto the skin asa layer of rich lather that quickly covers a wide area of skin, andbegins to relieve symptoms within about 2 minutes after application.

A second foam formulation is described in Table 9 below.

TABLE 9 Ingredient Amount (Weight %) Brimonidine tartrate 0.2-2 Water QSPalmitic Acid 2.12 Laureth-23 0.93 Triethanolamine (99%) 1.13 CetylDimethicone Copolyol 0.19 Mineral Oil 0.31 Stearyl Alcohol 0.31Lauramide DEA 0.15 PEG-150 Distearate 0.05 Imidazolidinyl Urea 0.0016Methylparaben 0.0005 Propylparaben 0.00003 Freeze Dried Aloe Powder0.0015 Fragrance 0.50 Aeron A-31 Propellant 3.00 TOTAL 100

The aqueous phase is prepared as follows. The water is heated to 80° C.,after which palmitic acid is added. Once the palmitic acid is melted,the laureth-23 is added, melted, and mixed well. Next, triethanolamineis added and the resulting composition is mixed well for about 15minutes to form a soap.

Stearyl alcohol, mineral oil, lauramide DEA, cetyl dimethicone copolyol,PEG-1 50 distearate, and BHT are mixed and heated at 55° C. to form theoil phase. The oil phase is combined with the aqueous phase at 80° C.and mixed well for about 15 minutes. The resulting mixture is thencooled to room temperature and the imidazolidinyl urea, methylparaben,and propylparaben are added, and then mixed well. The brimonidinetartrate is then added, and mixed well. Next, the fragrance is added,followed by gentle mixing. The aloe is then dissolved in make-up waterand added with slow mixing to form the product formulation which is thenpackaged in an aerosol can as described for the first foam formulation.

The product dispenses as a cone-shaped spray that deposits onto the skinas a layer of rich lather that quickly covers a wide area of skin, andbegins to relieve symptoms within about 2 minutes after application.

A third non-soapy foam formulation is described in Table 10 below.

TABLE 10 Ingredient Amount (Weight %) Brimonidine tartrate 0.4-0.6Ethanol 6 Ethyl Ester of PVM/MA 4 Copolymer Dimethicone Copolyol 0.1Water QS PVP/VA Copolymer 1 Sodium Lauryl Sulfate 1 Oleth-20 0.5Cocamide MEA 0.05 Methyl Paraben 0.1 Aminomethyl Propanol 0.53Stearalkonium Chloride 0.05 Steareth-16 0.1 Panthenol 0.5 Fragrance 0.5Aeron A-46 5 TOTAL 100

The alcohol phase is prepared by dissolving ethyl ester of PVM/MAcopolymer in ethanol, after which dimethicone is added and mixed well.The aqueous phase is prepared by heating the water to 65° C., afterwhich the PVP/VA copolymer is added and mixed well. The oil phase isprepared by mixing the oleth-20, cocamide MEA, and steareth-16 at 60° C.to form a blend. The oil phase is then added to the aqueous phase at 65°C. and mixed well. Next, the methylparaben is added to the mixture,followed by mixing, after which the aminomethyl propanol, stearalkoniumchloride, and panthenol are added and mixed until uniform. The resultingcomposition is cooled to room temperature, after which the alcohol phaseis added and mixed well. The fragrance is then added and mixed gently toform the product. The product is then packaged in an aerosol can.

The product dispenses as a cone-shaped spray that deposits onto the skinas a layer of rich lather that quickly covers a wide area of skin, andbegins to relieve symptoms within about 2 minutes after application.

Example 5 Photo Carcinogenicity Study with Brimonidine

Albino hairless SKH1-hr mice (36/sex/group) were treated for 40 weekswith UVR and brimonidine gel or vehicle according to the design in table11. Mice were further observed for 12 weeks without treatment. Topicaltreatments were performed approximately one hour before UVR on Monday,Wednesday and Friday of each week and approximately one hour after UVRTuesday and Thursday of each week. See table 11.

All procedures involving animals were conducted in a fully accreditedanimal facility and in accordance with the preapproved protocols.

TABLE 11 Add'l Period w/o Frequency of Solar- Duration of treatmentBrimonidine Administration administration simulated Treatment or UVRDosage tartrate (μL/mouse, on (days per UVR dose or exposure exposureGroup Conc. (%) 25 cm² BSA) wk)* (RBU/week) (weeks) (weeks) 1 Vehicle100 5 600 40 12 2 0.18 100 5 600 40 12 3 1 100 5 600 40 12 4 2 100 5 60040 12 5 N/A N/A N/A 600 40 12 6 N/A N/A N/A 1200 40 12 N/A: NOTAPPLICABLE RBU: Robertson-Berger Unit (a measure of effectiveness ofUVR; 400 RBU approximates one minimal erythema dose in previouslyuntanned human skin) *Monday, Wednesday and Friday of each week:exposure to UVR approximately one hour after test item application.Tuesday and Thursday of each week: exposure to UVR approximately onehour before test item application.

As the results shown in Table 12, topical application of Brimonidine at0.18%, 1%, and 2% concentrations surprisingly slowed down development ofskin tumor lesions. Brimonidine resulted in a dose-dependent delay inUV-induced skin tumor formation.

TABLE 12 Group Comparisons of Tumor Onset for Tumors ≧1 mm Group 1 Group2 Group 3 Group 4 Group 5 Group 6 Vehicle + 0.18% + 1% + 2% + (Notreatment) (No treatment) Parameter 600 RBU 600 RBU 600 RBU 600 RBU 600RBU 1200 RBU Median 40.5 48 >52 >52 40.5 26 Week(a) to Tumor (≧1 mm)Tumor Yield(b) 4.57 2.40 0.85 0.49 4.00 7.61 (≧1 mm) (a)The time atwhich one-half of the members of the groups have acquired one or morequalifying tumors. (b) Average number of tumors per survivor

The delay was observed in median week to tumor (≧1 mm) In fact, the 1%and 2% Brimonidine were so effective that less than one-half of themembers of the groups acquired one or more qualifying tumors within the52-week study period. The delay was also observed in tumor yield (≧1 mm)Compared to the vehicle group, 0.18% Brimonidine reduced the tumor yieldby 1.7-fold, 1% Brimonidine by 4.7-fold; and 2% Brimonidine by 8.1-fold.These results represent a significant delay in onset tumor formation.

Furthermore, FIG. 1 shows group comparisons of tumor prevalence. Notethat the number next each line denotes the treatment group number shownin Tables 11 and 12. As shown in FIG. 1, with increasing Brimonidineconcentration, the sizes of tumors were also reduced. This indicatesthat topical Brimonidine promote tumor regression as well.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

1. A method of preventing skin tumor formation in a subject in needthereof, comprising administering to the subject a compositioncomprising an effective amount of an α2 adrenergic receptor agonist anda pharmaceutically acceptable carrier.
 2. A method of inhibiting theprogression of an existing skin tumor in a subject in need thereof,comprising administering to the subject a composition comprising atherapeutically effective amount of an α2 adrenergic receptor agonistand a pharmaceutically acceptable carrier.
 3. A method of inducing thedeath or inhibiting the growth of a skin tumor cell, comprisingcontacting the skin tumor cell with a composition comprising an α2adrenergic receptor agonist in an amount sufficient to induce the deathor inhibit the growth of the skin tumor cell.
 4. A method for protectingthe skin, the lips, or the scalp of a subject in need thereof againstthe damaging effects of UV-radiation, comprising administering to thesubject a composition comprising a safe and effective amount of an α2adrenergic receptor agonist.
 5. A method of tanning the skin of asubject in a subject in need of, comprising administering to the subjecta composition comprising a safe and effective amount of an α2 adrenergicreceptor agonist.
 6. The method according to claim 2, wherein the α2adrenergic receptor agonist is selected from the group consisting of:brimonidine,(8-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(8-Bromo-quinoxalin-5-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(5-Bromo-3-methyl-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(5-Bromo-2-methoxy-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(4,5-dihydro-1H-imidazol-2-yl)-(8-methyl-quinoxalin-6-yl)-amine,(4,5-dihydro-1,4-imidazol-2-yl)-quinoxalin-5-yl-amine, naphazoline,tetrahydrozaline, oxymetazoline, xylometazoline, epinephrine,norepinephrine, phenylephrine, and methoxamine.
 7. The method accordingto claim 2, wherein the composition comprises from about 0.01% to about5% by weight of the α2 adrenergic receptor agonist.
 8. The methodaccording to claim 7, wherein the composition comprises from about 0.1%to about 2% by weight of the α2 adrenergic receptor agonist.
 9. Themethod according to claim 2, wherein the composition is administered tothe subject through the route of topical, epicutaneous, transdermal,subcutaneous, or intramuscular delivery.
 10. The method according toclaim 9, wherein the composition is administered to the subject bysubcutaneous delivery to the skin area in need such administration. 11.The method according to claim 9, wherein the composition is administeredto the subject by topical application onto the skin in need suchadministration.
 12. The method of claim 2, wherein the skin tumor isselected from the group consisting of papilloma, actinic keratosis, abasal cell carcinoma, a squamous cell carcinoma, keratoacanthoma, amelanoma, a sarcoma, and a lymphoma.
 13. The method of claim 2, furthercomprising administering to the subject another treatment or activeingredient for preventing or treating skin tumor.
 14. A cosmetic productcomprising: (1) a topical composition comprising a safe and effectiveamount of an α2 adrenergic receptor agonist; and (2) instructions onapplying the topical composition to the skin, the lips, or the scalp ofa subject against the damaging effects of UV-radiation.
 15. The cosmeticproduct of claim 14, wherein the topical composition further comprises asafe and effective amount of a sun screening agent.
 16. A topicalcomposition for tanning the skin of a subject in need thereof,comprising (1) a safe and effective amount of an alpha 2 adrenergicreceptor agonist, and (2) a safe amount of a tanning agent.
 17. Thetopical composition of claim 16, wherein the tanning agent is selectedfrom the group consisting of tyrosine, riboflavin, collagen hydrolysate,and combinations thereof.
 18. The topical composition of claim 16,wherein the α2 adrenergic receptor agonist is selected from the groupconsisting of: of brimonidine,(8-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(8-Bromo-quinoxalin-5-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(5-Bromo-3-methyl-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(5-Bromo-2-methoxy-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,(4,5-dihydro-1H-imidazol-2-yl)-(8-methyl-quinoxalin-6-yl)-amine,(4,5-dihydro-1H-imidazol-2-yl)-quinoxalin-5-yl-amine, naphazoline,tetrahydrozaline, oxymetazoline, xylometazoline, epinephrine,norepinephrine, phenylephrine, and methoxamine.
 19. The compositionaccording to claim 18, wherein the composition comprises from about0.01% to about 5% by weight of the α2 adrenergic receptor agonist. 20.The composition according to claim 18, wherein the composition comprisesfrom about 0.1% to about 2% by weight of the α2 adrenergic receptoragonist.
 21. A method of preventing skin tumor formation in a subject inneed thereof, comprising administering to the subject a compositioncomprising an effective amount of brimonidine and a pharmaceuticallyacceptable carrier.
 22. A method of inhibiting the progression of anexisting skin tumor in a subject in need thereof, comprisingadministering to the subject a composition comprising a therapeuticallyeffective amount of brimonidine and a pharmaceutically acceptablecarrier.
 23. A method of inducing the death or inhibiting the growth ofa skin tumor cell, comprising contacting the skin tumor cell with acomposition comprising brimonidine in an amount sufficient to induce thedeath or inhibit the growth of the skin tumor cell.
 24. A method forprotecting the skin, the lips, or the scalp of a subject in need thereofagainst the damaging effects of UV-radiation, comprising administeringto the subject a composition comprising a safe and effective amount ofbrimonidine.
 25. A method of tanning the skin of a subject in needthereof, comprising administering to the subject a compositioncomprising a safe and effective amount of brimonidine.
 26. A cosmeticproduct comprising: (1) a topical composition comprising a safe andeffective amount of brimonidine; and (2) instructions on applying thetopical composition to the skin, the lips, or the scalp of a subjectagainst the damaging effects of UV-radiation.
 27. A topical compositionfor tanning the skin of a subject in need thereof, comprising (1) a safeand effective amount of brimonidine, and (2) a safe amount of a tanningagent.